Coccidiosis control with quinalinol derivatives

ABSTRACT

VETERINARY COMPOSITIONS FOR THE PREVENTION AND CONTROL OF POULTRY COCCIDIOSIS WHICH COMPRISES A SOLID OR LIQUID INGESTIBLE CARRIER AND DISPERSED THEREIN COMPOUNDS OF THE GENERAL CONFIGURATION:   2-(CH3-),3-R1,4-(HO-),6-R2,7-R3-QUINOLINE   WHREIN R1 IS H OR ALKYL GROUPS WITH 1 TO 12 CARBON ATOMS AND R2 AND R3 ARE H, OH, OR ALKOXY SUBSITUENTS WITH 1 TO 12 CARBON ATOMS AND PHYSIOLOGICALLY ACCEPTABLE SALTS OF SUCH COMPOUNDS. THE COMPOUNDS 3-N-HEPTYL-7METHOXY-2-METHYL-4-QUINOLINOL IS DESCRIBED AS AN EXAMPLE.

United States U.S. Cl. 424-258 5 Claims ABSTRACT OF THE DISCLOSURE Veterinary compositions for the prevention and control of poultry coccidiosis which comprises a solid or liquid ingestible carrier and dispersed therein compounds of the general configuration:

(IDH

R1 \Nl wherein R is H or alkyl groups with 1 to 12 carbon atoms and R and R are H, OH, or alkoxy substituents with 1 to 12 carbon atoms and physiologically acceptable salts of such compounds. The compounds 3-n-heptyl-7- methoxy-2-methyl-4-quinolinol is described as an example.

This invention relates to prophylactic and curative compositions for and methods of treatment and control of poultry coccidiosis. Avian coccidiosis is a widely prevalent infection among chickens, turkeys, and other domesticated birds. It is caused by a genus of protozoal parasites known as Eimeria, among which Eimeria tenella, Eimeria necatrz'x, Eim rz'a acervulina, Eimeria brunetti, and Eimeria maxima are the most common species with varying degrees of harrnfulness and virulence. While some etiological factors of this epizootic, such as Eimeria tenella and Eimeria necatrix, are especially destructive to the point of large scale mortality, the pathogenicity of others manifests itself primarily in a state of lingering morbidity, unthriftiness and progressive emaciation, exposing the afflicted flocks to numerous secondary bacterial and viral infections. Economic losses due to coccidiosis amount to many millions of dollars, which compels the poultry industry to seek new and improved means for controlling coccidial infections that have a broad spectrum of efiicacy, do not adversely affect the normal physiological functions of the birds, and are economical in use.

We have found that chemical compounds having the aforesaid desirable properties are represented by the following configuration:

wherein R is H or alkyl groups with l to 12 carbon atoms and R and R are H, OH, or alkoxy substituents with 1 to 12 carbon atoms. Physiologically acceptable salts of these compounds may likewise serve as active ingredients in our novel veterinary compositions.

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3,636,216 Patented Jan. 18, 1972 Our invention will be illustrated by the compound 3- n heptyl 7 methoxy 2 methyl 4 quinolinol, having the structure:

also known under the name of Endochin, and its hydrochloride salt. The chemical is obtained in form of White needles, has a melting point of 2l8.52l9.5 C. is soluble in alcohol and acetic acid and completely insoluble in water. Its synthesis from m-anisidine has been described by Nelson J. Leonard and co-workers in the J. Am. Chem. Soc., 68, 1279ff (July 1946).

In accordance with our invention the above-defined chemotherapeutic agents, in general, and Endochin and its hydrochloride, in particular, are advantageously employed by introducing the same into the animal organism in any form or manner in which they are apt to build up and maintain an effective blood and tissue level. This can be accomplished either by injection or by dispensation of suitable nontoxic dosage units in capsules or tablets. However, as a preferred embodiment of our invention the compounds are administered to the animals in combination with and dispersed in a solid, inert, and nontoxic vehicle in which they are uniformly and homogeneously dispersed. Inactive carriers of ingestible nature are any kind of vegetable food material such as ground corn, cornmeal, dried distillers grain, citrus meal, ordinary grain, mash, scratch, and any other normal or commercial rations. The so-medicated feed rations are placed before the birds for consumption ad libitum. The compounds may also be used as active ingredients in liquid compositions which can be conveniently prepared by means of drinking water, in which they are. dissolved or suspended by the help of skim milk, edible oils, syrups, wetting agents, and emulsifiers.

The new drugs are principally, but not exclusively, intended for prophylactic purposes to prevent the eruption and spread of a latent infection, and to this eifect are to be dispensed on a continuous schedule. When, for instance, an impending outbreak of coccidiosis in a natural flock is suspected by reason of exposure or the sporadic appearance of the first clinical symptoms of the disease, the remedies are administered to the birds for approximately two weeks and even for a longer period if the infection is of more serious nature.

The minimum dosage in the feed for protecting the birds from a coccidiogenic infection was established at 0.0125 but this may be increased with superior results to the preferred concentration of 0.05%. These effective, but nontoxic, dosages may slightly vary depending upon the specific compound selected and the. particular pathogenic Eimeria involved.

The utility of our new veterinary compositions will be illustrated by a number of tests against Eimeria acervulina, Eimeria necatrix, and Eimeria brunetti. The drug serving as a representative example was Endochin and its hydrochloric acid salt.

For each experiment, perfectly healthy 4Vz-Week-old Leghorn chickens, in groups of 4, were. reared in an aseptic environment and prepared for test fitness. Each bird was weighed starting on the first and continuing to the last day of the experiment. In order to determine the efficacy of the drug, each of the birds was placed on medicated food 2 days before artificial inoculation and successively maintained thereon for 8 to 13 days. For artificial challenges, the birds received, respectively, 5 to 10,000,000

on the basis of their magnitude and conformity with the following ratings:

0-droppings normal +droppings slightly abnormal a oocysts of Eimeria acervulina, 200,000 oocysts of Et'meria fig g h g normal: 1 brunetti, and 100,000 oocysts of Eimeria necazrix. A ref- 7 g h a 0 i g g Hernia erence group of 4 birds was infected but left Without T+++ r Ppmgs comp e ey a norma medication and served as controls. A third group of 4 The morbidity factor eXPTeSSeS the comparative Values birds was neither challenged nor treated with medicated 10 between Weight gains of medicated, infected birds on the rations, The activity of th drugs was l t d i terms one hand and nonmedicated, noninfected controls on the of comparative fecal scores nd o bidit f t d other and, further, a comparison between weight gains of in the case of Ez'meria necatrix, of mortality rates. medicated, infected birds and infected, nonmedicated Beginning on th fourth d ft i t l i 1 birds or controls. During the interval between the 5th and tion and every day thereafter until the conclusion of the 7th y the eeeehhal infection Ordinarily Causes the maxi experiment, the droppings f h him were a ef ll mum inhibition of growth, which reflects itself in the examined and their deviations from the normal appearultimate Weight gains of 105565 at the COHCluSiOIl 0f the ance were graded in accordance with accepted practice test p Assuming the mean Weight increase of the as fecal scores, which were computed in the following infected, medicated group in a given eXlPefhheht is 68 manner. In the case of Eimerz'a necatrix, which produces g While that Of the hellihfeeted, nollmedieated birds hemorrhage, the amount of hemorrhage in the droppings i5 129 the ratio of collected in metal pans beneath the birds were rated and 3 recorded in terms of: X 100 =53% no hemofrhage would present the morbidity factor and indicate that the B 1i hemorrhage test birds had a growth rate drop of 100- 53%=47%. If, BB hemorrhage on the other hand, the morbidity factor of the infected but BBB severe hemorrhage nonmedicated controls is 5, the growth rate drop for that B B severe hemorrhage group would be 1005%=95%. The difference between the two growth rate drops would be 9547%:48%, and Upon the o l io of h test, the maximum hfimop reflects the fact that the stunting effect of the infection rhage rating for each bird, irrespective of the day of its was compehsateh by the drug to the h h 5 Occurrence, w r d d, All h maximum ratings for In the following table the column indicating the test the medicated, infected groups were totaled and comnumber is followed by the name of the hh hhdhr pared with th t t l f th maximum ratings f the investigation and thereupon by the specific cocc1d1ogen1c medicated, infected controls. If the artificial infections had Organism which was tested and the concentration of the taken effective hold, each of the 4 infected and nondrug in the feed- Under the heading Schedhlg the [first medicated bird would h a full rating f BBBB during figure in the abbreviated term designates the number of at, least one day of th t t i d so h h maximum feed medication days prlor to the infection, and the total rating for that group ld ll amount to 16 second, in parenthesis, the total number of medication Bs. Supposing the highest ratings f f i fe t d and days. Thus, for instance, 22-11 03) means that the buds medicated birds in a given group are, respectively, 0, BB, F Placed on medleated Chet two y? Prior to B, and B, the total rating for the entire group would be artificial hloehlaheh and h the g was glVeh for a 4 Bs. The difference between the B-totals divided by the total of 13 days, or 11 addlhohal y Subsequent to the maximum rating established for the infected, non- 5 ehahehgemedicated controls times 100 represents the fecal score, The next columns hst the fecal scores and the average thus weight gains in grams. They are followed by the morbidity factor (MF%), the growth rate drop (GRD%), and finally the compensating efiect (CE% as previously 16 4=12; 1Q0=75% explained. The final two columns are specifically set up 16 for Eimeriw necatrix, which causes an appreciable rate of mortality. The first records the actual number of birds A fecal score of therefore, means that the droppings which have succumbed to the disease and the second were 75% normal. translates these figures into percentages.

TABLE Feed Av. Wt. Mortality, cone, Fecal gains, MF, GRD, I No.01 Test No. Compound Parasite percent Schedule score gms percent percent percent dead Percent 1 Uninfected 182 100 E. acertmlma 0 36 20 8O 0. 0125 2IF(13) 0 0.0125 2IF(13) 0. 0250 2IF(13) 0. 0250 2-1F(13) E. acarvulina :::IIIIIII: 6 Endochin 0.0500 2IF(8) 1 Yamagata; 1.- "'aiaan rnn'i 2 EndochinJEEO 0. 0250 2IF(13) E. amine. I::IIIIIIIIIIIII: 1 Endochin 0.0500 2-IF(9) 7.. Umnfected 8 E. lmmettz 0 0 Endochin 0. 0500 2 mm 100 In a similar manner, the fecal scores for the species causing no appreciable hemorrhage, but other character- As can be seen from the foregoing table, Endochin and its hydrochloride salt are potent remedies in the control istic clinical deviations in the droppings, are computed 75 of a variety of coccidiogenic organisms at the indicated dosage levels. In Experiment 5, for instance, the fecal score is improved by almost 50% over that of the infected controls, While the compensating effect on the drug checks the growth rate drop by 17% in an Eimeria acervulz'na infection. As shown in Experiment 13, Endochin hydrochloride controls Eimeria necatrix in terms of a fecal score of 75%, and not only completely prevents the total growth rate drop of the infection, which is 91%, but even overcompensates the rate to an extent of 3%, which is actually an indication of growth promotion activity despite the disease. The tests on Eimeria necatrix further show that the mortality rates at the level of 0.025% and 0.05% are 0, which means that the drugs afford 100% protection against death losses. Specifically, in Experiment 16, no growth rate drop and compensating effect could be computed, as all the infected controls had died prior to the completion of the experiment.

The preparation of the medicated feed compositions was carried out by intimately mixing the active ingredients with an orally ingestible carrier material such as feed in an amount of 20-50% by weight and introducing a proportionate quantity of this premix into the bulk of a commercial feed ration with thorough stirring and shuffling until a uniform blend of even distribution at the desired concentration between approximately 0.0125 and 0.05% was obtained. Commercial feed rations of the type employed in our experiments included the normal constituents in a mash or scratch supplemented with desirable amounts of vitamins, trace minerals, antibiotics, growth stimulants, and preservatives; the addition of which, however is optional.

To facilitate the handling of the small amounts of chemicals to be incorporated into the ultimate medicated ration, the premix can also be prepared by grinding a limited quantity of a nontoxic inert vehicle with an amount of up to 95% by weight of the drug. In this case, the carrier material may consist of fullers earth, talcum, bentonite, ground oyster shells, limestone, and divers clays, or edible feed substances such as soybean meal, wheat middlings, and cornmeal and such stock concentrates are specifically made and adapted for use in dilutions with an edible carrier so as to compound the medicated rations at the desired dosage levels with utmost convenience. The availability of such concentrates is therefore highly desirable, if not indispensable, for the feed manufacturer and poultry raiser who ordinarily uses about one pound of the premix or concentrate for each ton of commercial feed to produce the finished medicated ration. 7

What we claim is:

1. A method for the control of coccidiosis in poultry comprising the step of orally administering to poultry an eifective but nontoxic amount of 3-n-heptyl 7 methoxy- Z-methyl 4 quinolinol or its physiologically acceptable salts.

2. A method for the control of coccidiosis in poultry which comprises adding to the feed ration of poultry, a quantity sufficient to provide 0.0125% to 0.05 by weight of 3-n-heptyl 7 methoxy 2 methyl-4-quinolino1 or its physiologically accepted salts, and feeding the ration to poultry.

3. A method for the control of coccidiosis in poultry comprising the step of administering orally to poultry a composition consisting of a nontoxic orally ingestible carrier and 0.0125% to 0.05% 'by weight of 3-n-heptyl- 7-methoxy 2 methyl 4 quinolinol or its physiologically accepted salts.

4. The method as defined in claim 3 wherein the nontoxic orally ingestible carrier is a poultry feed.

5. The method as defined in claim 3 wherein the nontoxic orally ingestible carrier is drinking water.

OTHER REFERENCES Salzer et al., Chem. Abst., vol. 43 (1949), p. 1415c.

SAM ROSEN, Primary Examiner 

